Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma

Calcitriol [1,25(OH)(2)D-3], the hormonal derivative of vitamin D-3, is an antiproliferative and prodifferentiation factor for several cell types, inc luding cultured melanocytes and malignant melanoma (MM) cells, Several poly morphisms of the vitamin D receptor (VDR) gene have been described includin g a FokI RFLP in exon 2, BsmI, and ApaI polymorphisms in intron 8 and an ad jacent TaqI RFLP in exon 9. Alterations in vitamin D/1,25(OR)(2)D-3 levels and polymorphisms of the VDR have been shown to be associated with several systemic malignancies. We hypothesize that polymorphism in this gene may be associated with altered susceptibility and outcome in patients with MRT. A hospital-based case-control study, using 316 MM cases and 108 controls, wa s used to assess associations with MM susceptibility. Breslow thickness, th e most important single prognostic factor in MM, was used as the outcome me asure. Polymohrphisms at the FokI and TaqI restriction sites were determine d using PCR-based methods. Polymorphism at the FokI, but not TaqI RFLP was associated with an altered risk of MM (P = 0.014). More importantly, varian t alleles were associated with increased Breslow thickness. Thus, homozygos ity for variant alleles at both RFLP (ttff genotype combination) was signif icantly associated with thicker tumors. (greater than or equal to 35 mm; P = 0.001; odds ratio = 31.5). Thus, polymorphisms of the VDR gene, which wou ld be expected to result in impaired function, are associated with suscepti bility and prognosis in MM. These data suggest that 1,25(OH)(2)D-3, the lig and of the VDR, may have a protective influence in MM as has been proposed for other malignancies.